Traumatic brain injury contributes substantially to morbidity and mortality in the United States. Despite active research, treatment options for traumatic brain injury are limited and the outcome of severe traumatic brain injury remains poor. Recently, acid sensing ion channel 1a (ASIC1a) was shown to play a significant role in the cell death processes following cerebral ischemia and demyelination. Administration of ASIC1a antagonists protected against the effects of ischemia in a mouse model of stroke and resulted in smaller infarct size. Likewise, administration of ASIC antagonists in a mouse model of demyelination led to improved functional outcome. Given the role of ASIC1a following stroke and demyelination, it is likely that ASIC1a also contributes to cellular damage following traumatic brain injury. The role of ASIC1a in traumatic brain injury will be examined using the lateral fluid percussion model of traumatic brain injury in mice. The role of ASIC1a in contributing to neuron death and poor outcome following traumatic brain injury will be investigated using knock-out mice with a targeted disruption of ASIC1a and transgenic mice overexpressing ASIC1. In addition, wild type mice will be treated with ASIC antagonists following traumatic brain injury in order to investigate ASIC1a as a therapeutic target. Finally, since cerebral pH changes are likely important in the activation of ASIC1a, in vivo pH measurements will be made in mice before and after induction of traumatic brain injury. The results of these experiments will begin to define the role of ASIC1a in the pathophysiology of secondary injury due to traumatic brain injury. Success with these studies would suggest ASIC1a as a new target for pharmacologic treatment of patients following traumatic brain injury. PUBLIC HEALTH RELEVANCE: Traumatic brain injury contributes significantly to death and disability in the United States. Despite active research, treatments for traumatic brain injury are limited and outcomes from severe traumatic brain injury remain poor. Acid sensing ion channels are a potentially new therapeutic target in the treatment of traumatic brain injury. [unreadable] [unreadable] [unreadable]